Patients who have been immunologically sensitized by a previous transplant, pregnancy, or blood transfusion may not receive a renal transplant due to our current difficulty preventing rejection in such patients. In addition, patients successfully transplanted have an approximately 20% risk of developing B cell sensitization to their functioning kidney allograft and of alloantibody shortening the life of their kidney. Costimulation blockade, in particular agents targeting CD28 and CD40, may offer significant advantages over conventional immunosuppressive agents in preventing and overcoming an alloantibody response. CD28 has recently been shown to be expressed on long-lived plasma cells in bone marrow and necessary for their survival and continued antibody production. Our rodent model data suggest that costimulation blockade may be able to down regulate the B cell response in a donor-specific manner. In order to move toward clinical application in humans, we propose to test costimulation blockade in combination with other putative agents including Belimumab (anti-BAFF), anti-APRIL and Bortezomib (proteasome inhibitor) that target the sensitized immune repertoire of NHP's. We plan to test the ability of such agents alone and in combination with donor bone marrow infusion in order to achieve donor-specific desensitization in a clinically relevant rhesus monkey renal allograft model. Briefly, the model uses monkeys sensitized by a previously rejected renal allograft, and ultimately we aim to achieve immunologic unresponsiveness to a second kidney transplanted from the same donor. We will use state of the art methods developed by us to measure not only T and B cell sensitization and desensitization, but also will measure the affect of treatment on the protective immune response that must remain intact for avoidance of infection. We will build upon lessons learned from our previous UOI grant that focused on the T and B cell response in monkeys developing de novo antibody after renal transplantation. We have already learned that CD28 blockade with Belatacept effectively prevents alloantibody from developing in a rigorous NHP model. We now propose to use a difficult but yet more clinically relevant NHP model to evaluate strategies to desensitize the host.